A Defect in Mitochondrial Function May Underlie Chronic Fatigue Syndrome

Although the pathophysiology of chronic fatigue syndrome (CFS) remains poorly understood, recent research suggests that a defect in mitochondrial function may underlie the disease. A study has revealed that the peripheral blood mononuclear cells (PBMCs) of patients with CFS are unable to meet certain energetic demands. According to a study by Cara Tomas, a graduate student at Newcastle University in the U.K., and colleagues, this mitochondrial limitation is apparent under basal conditions, as well as during periods of high metabolic demand. The investigators published their research online on Oct. 24 in PLOS One.1

The team performed mitochondrial stress tests on freshly isolated PBMCs, as well as on PBMCs that were frozen at -80◦C on the day of collection and revived for experimentation. The investigators used the cells to measure seven parameters of respiration: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, nonmitochondrial respiration and coupling efficiency. They found significantly altered mitochondrial stress parameters in PBMCs from patients with CFS compared with PBMCs from healthy control individuals. The differences spanned four parameters: basal respiration, proton leak, maximal respiration and reserve capacity.

However, the researchers note that the freezing process elicited a significant effect on the cellular bioenergetics of PBMCs from patients with CFS, as well as PBMCs from healthy individuals. They believe these differences to be a result of stress from the freezing process. In particular, when they compared fresh and frozen PBMCs, they saw differences in basal respiration, ATP production, maximal respiration and reserve capacity. Although freezing did affect certain parameters from both cohorts, the same parameters were significantly different between the CFS and control cohorts.

The investigators then sought to measure mitochondrial response to the natural stressor of hypoglycemia. They performed the mitochondrial stress tests in low (1 mM) and high (10 mM) glucose concentrations and found basal respiration, ATP production, maximal respiration and reserve capacity differed between the control and CFS cohorts. In particular, maximal respiration stood out as a key parameter of mitochondrial function that differed between CFS and control PBMCs.

The investigators propose that PBMCs from healthy individuals can adapt to environmental stressors by enhancing their ability to increase ATP production through mitochondrial respiration. In contrast, PBMCs from patients with CFS lack this ability. Their hypothesis was supported by the fact that, when they tested coupling efficiency under the stress of low glucose conditions, ATP production was efficient in the control cohort, but not the CFS cohort.

Thus, the authors conclude that the lower maximal respiration seen in CFS PBMCs may indicate the cells are unable to elevate their respiration rate to compensate for the increased cellular energy demands experienced during physiological stress. They also note that their experiments could not determine whether the differences in PBMC energy patterns are a cause or consequence of CFS. However, investigators suggest that future research focus on maximal respiration in the mitochondria of patients with CFS.